Pseudo-Mannosylated DC-SIGN Ligands as Immunomodulants

Abstract

DC-SIGN, a C-type lectin mainly expressed by DCs, mediates antigen uptake and can induce specific immune responses, depending on the ligand involved. Owing to these properties, DC-SIGN is an attracting target for approaches aimed at tailoring the immune response towards specific immunologic outcomes. A multivalent DC-SIGN ligand (Polyman26), containing at its core a fluorescent “rod-like” spacer and able to inhibit DC-SIGN mediated HIV infection in nanomolar concentration, has been recently developed by our group. We investigated the internalization pattern and the ability of Polyman26 to elicit innate immune responses. Results obtained by confocal microscopy indicate that Polyman26 is internalized by DCs via receptor- mediated endocytosis and is then routed to endolysosomal compartments, thus being presented together with MHC class II molecules, with important implications for the development of vaccines. Moreover, Polyman26 up-regulated the production of β-chemokines and pro-inflammatory cytokines (including IL-1β, IL-6, IL-12, and TNFα) as well as the expression of TLR9 and CD40L. These results indicate that glycomimetic DC-SIGN ligands should be further investigated and suggest that these compounds could be used to differentially stimulate immune responses.

DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist

“…DC/L-SIGN antagonists may help reducing the severity of SARS-CoV-2 infection by inhibiting the trans-receptor role played by these CLRs. We show here that was shown to induce a pro-inflammatory anti-viral response (Berzi et al, 2016), which should be beneficial at the onset of the infection and may help to steer the immune response towards a profile correlated with milder forms of the disease.…”

“…Polyman26 (PM26, Figure 6A) is a multivalent glycomimetic mannoside tailored for optimal interaction with DC-SIGN (Ordanini et al, 2015). It is known to bind DC-SIGN carbohydrate recognition domain (CRD), eliciting a Th-1 type response from human immature monocyte derived dendritic cells (Berzi et al, 2016). It also inhibits DC-SIGN mediated HIV infection of CD8 + T lymphocytes with an IC50 of 24 nM (Ordanini et al, 2015).…”

Dendritic Cells in Anticancer Vaccination: Rationale for Ex Vivo Loading or In Vivo Targeting

“…Flexible platforms that represent the targeting vector with self-adjuvant properties will be required as a basis to enable the possibility of personalized vaccines. Examples of such platforms, such as Clec9A-specific nanoemulsions, Lipovaxin and Polyman26, already exist [46,90,131]. Thus, only the substitution of necessary antigens will be required.…”

“…Such particles were found to be neutral toward maturation and IL-10 production. Another approach is to use the so-called Polyman26, which is a glycodendrimer that includes a linear rigid spacer at its core [90]. It has been shown that Polyman26 was efficiently internalized by moDCs via DC-SIGN-mediated endocytosis and then routed to early endosomal and endolysosomal compartments.…”

“…Heat shock proteins are one example of SR ligands that can be utilized to achieve DC targeting and activation at the same time [157]. Different nanosubstance-based approaches might be also helpful, since several nanosubstances utilized to deliver tumor antigens to a specific DC receptor, such as glycodendrimers and nanoemulsions, have been shown to be self-adjuvant [90,131,190].…”